A-Kinase Anchoring Protein 1: Emerging Roles in Regulating Mitochondrial Form and Function in Health and Disease

Abstract

Best known as the powerhouse of the cell, mitochondria have many other important functions such as buffering intracellular calcium and reactive oxygen species levels, initiating apoptosis and supporting cell proliferation and survival. Mitochondria are also dynamic organelles that are constantly undergoing fission and fusion to meet specific functional needs. These processes and functions are regulated by intracellular signaling at the mitochondria. A-kinase anchoring protein 1 (AKAP1) is a scaffold protein that recruits protein kinase A (PKA), other signaling proteins, as well as RNA to the outer mitochondrial membrane. Hence, AKAP1 can be considered a mitochondrial signaling hub. In this review, we discuss what is currently known about AKAP1′s function in health and diseases. We focus on the recent literature on AKAP1′s roles in metabolic homeostasis, cancer and cardiovascular and neurodegenerative diseases. In healthy tissues, AKAP1 has been shown to be important for driving mitochondrial respiration during exercise and for mitochondrial DNA replication and quality control. Several recent in vivo studies using AKAP1 knockout mice have elucidated the role of AKAP1 in supporting cardiovascular, lung and neuronal cell survival in the stressful post-ischemic environment. In addition, we discuss the unique involvement of AKAP1 in cancer tumor growth, metastasis and resistance to chemotherapy. Collectively, the data indicate that AKAP1 promotes cell survival throug regulating mitochondrial form and function. Lastly, we discuss the potential of targeting of AKAP1 for therapy of various disorders.

Compartmentalized Signaling in Aging and Neurodegeneration

“…In addition, AKAP1 is involved in neuronal development [ 101 ], as demonstrated by experiments in cultured hippocampal neurons, where increasing AKAP1 levels increased dendritic outgrowth and reduced the number of synapses [ 102 ]. AKAP1 tethers at the OMM both PKA and the opposing phosphatases PP1 and Calcineurin (CaN) [ 103 ], coordinating mitochondrial fission/fusion through the regulation of the Drp1 phosphorylation extent. Specifically, PKA-dependent phosphorylation of Ser637 inhibits Drp1 and prevents fission, which results in elongated mitochondria [ 78 , 104 ].…”

AKAP1 Deficiency Attenuates Diet‐Induced Obesity and Insulin Resistance by Promoting Fatty Acid Oxidation and Thermogenesis in Brown Adipocytes

“…[ 8 ] The mitochondria‐localized AKAP1 tethers PKA to the cytosolic surface of the outer mitochondrial membrane (OMM) in close proximity of local targets to maintain the mitochondrial function. [ 9 ] A previous study has reported that AKAP1 expression is significantly downregulated in adipose tissues of obese subjects when comparing with lean subjects. [ 10 ] Moreover, other studies have revealed the phenomenon that disruption of PKA regulatory subunit in mice leads to a lean phenotype.…”

Epigenetic silencing of microRNA‑199a‑5p promotes the proliferation of non‑small cell lung cancer cells by increasing AKAP1 expression

“…4A ). Recently, the unique involvement of AKAP1 in tumor growth has been reviewed ( 14 ). In the present study, the luciferase assay results demonstrated that miR-199a-5p inhibited the activity of the reporter with wild-type 3′UTR of AKAP1 mRNA, but was not able to change the activity of the reporter when the miR-199a-5p binding site was mutated ( Fig.…”

“…A-kinase anchoring protein 1 (AKAP1) is a scaffold protein, which recruits protein kinase A, other signaling proteins and RNA to the outer mitochondrial membrane ( 14 ). In hepatocellular carcinoma, high expression levels of AKAP1 are associated with a poor prognosis, suggesting that AKAP1 may serve as a biomarker ( 15 ).…”